Histological Characterization of Microlesions Induced by Myocardial Contrast Echocardiography

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Abstract
Myocardial contrast echocardiography (MCE) has been shown to have a potential for apparently reversible side effects related to the interaction of ultrasound with the contrast microbubbles, including premature ventricular contractions and microvascular leakage. We investigated the potential for high-dose MCE to induce histologically definable microlesions. Myocardial contrast echocardiography with 1:4 end-systolic triggering was performed at 1.5 MHz and 1.7 mechanical index in a short axis view of the left ventricle in rats. Two high doses (500 microl/kg) of Optison agent were given 5 minutes apart during 10 minutes of echocardiography. For histology, the hearts were perfused and fixed in 10% neutral-buffered formalin. Slides from rats sacrificed 1 day after MCE were scored blind by a pathologist, and, in addition, photomicrographs in the anterior half were evaluated by digital image analysis. In rats sacrificed 10 minutes after MCE, microvascular leakage and petechiae were highly significant. However, lesions displaying necrotic debris associated with inflammatory infiltrates were not histologically evident at this time. Heart samples 24 hours after MCE showed microlesions with inflammatory infiltrates scattered primarily over the anterior half of the sections. Pathologically, there was inflammatory cell infiltration in areas of 0.6 +/- 0.5% for shams and 3.6 +/- 3.6% for MCE (P < 0.01). Analysis of photographs from the anterior wall found microlesion areas of 0.5 +/- 0.8% for shams and 7.4 +/- 5.0% for MCE (P < 0.02). For rats sacrificed 1 week and 6 weeks after MCE, the microlesions healed to form small fibrous regions interspersed with normal myocytes. High-dose MCE has a potential for causing microscale lesions in the myocardium and the possibility of therapeutic applications.